P-059: TRIAL IN PROGRESS: THE RANDOMIZED, DOUBLE-BLIND, MULTICENTER, PLACEBO-CONTROLLED PHASE 3 RESOLVE TRIAL INVESTIGATING THE EFFICACY OF VOXELOTOR WITH STANDARD OF CARE IN THE RESOLUTION OF LEG ULCERS IN PATIENTS WITH SICKLE CELL DISEASE
Authors: MINNITI C., BRADLEY S., DOSS J., PURDIE D., HOPPE C., CROUCH A.
Journal: HemaSphere (2022)

Purpose: Sickle cell disease (SCD) is a heritable blood disorder caused by a point mutation in the β-globin gene. Polymerization of deoxygenated mutated hemoglobin is the major molecular process in SCD pathogenesis that leads to red blood cell sickling and hemolysis. In addition to the major complications of SCD—hemolytic anemia, inflammation, and vascular occlusion—patients often experience secondary complications such as stroke, organ damage, shortened lifespan, and painful and debilitating skin ulcers. The prevalence of leg ulcers among people with SCD is likely underestimated, given the lack of registries and large prospective studies examining this complication. Current estimates of leg ulcers vary widely by geographic region: 43% in Brazil, 30% in Jamaica, 27% in Nigeria, 19% in Ghana, 13% in Sierra Leone, 8% in Saudi Arabia, and 1%-5% in the US. Among Americans with SCD, an estimated 14%-18% may develop leg ulcers. Voxelotor, a sickle hemoglobin polymerization inhibitor, is approved in the US for the treatment of SCD in adults and pediatric patients aged ≥4 years and in the EU for the treatment of hemolytic anemia due to SCD in adults and pediatric patients aged ≥12 years as a monotherapy or in combination with hydroxycarbamide. In a post hoc analysis of voxelotor-treated patients from the phase 3 HOPE study (NCT03036813), leg ulcers resolved within 24 weeks in 10 out of 14 patients, and leg ulcers improved or resolved in 13 out of 14 patients by week 72. Materials and methods: RESOLVE is an ongoing phase 3, randomized, double-blind, placebo-controlled, multicenter trial investigating the efficacy of voxelotor with standard of care (SOC) in the resolution of leg ulcers in patients with SCD. Target enrollment is 80 patients from Nigeria, Kenya, and Brazil with a confirmed diagnosis of SCD (HbSS or HbSβ0 genotype), aged ≥12 years, and with ≥1 cutaneous ulcer on the lower extremity (leg, ankle, or dorsum of foot) that meets the following criteria: ≥2 weeks’ and <6 months’ duration at screening and >2 cm2 in area before randomization. After a 2-week run-in period, participants are randomized 1:1 to receive once-daily oral voxelotor 1500 mg or placebo in addition to SOC for 12 weeks. After the randomized treatment period, all participants receive open-label voxelotor 1500 mg plus SOC for 12 weeks (Figure). Results: The primary objective of the study is to assess the efficacy of voxelotor plus SOC compared with placebo plus SOC on leg ulcer healing, measured by the proportion of patients with resolution of target ulcer(s) in each treatment group by week 12. Key secondary endpoints include days to resolution of target ulcer(s) up to week 12, change from baseline in total surface area of target ulcer(s) at week 12, and incidence of new ulcers by week 12. Conclusion: Results from this study will further guide clinicians and patients regarding the clinical use of voxelotor for the treatment of leg ulcers in patients with SCD. Participants will have the option to enroll in a separate open-label extension study after the 24-week treatment period.Figure. RESOLVE Study Design, Population, and Timeline J. DOSS declares a conflict of interest: Stock shareholder: Global Blood Therapeutics, Roche